General Considerations

The presentation of patients with tumors that occur in the thalamus, pineal gland, and brainstem share many characteristics with brain neoplasms in general, including headaches, hemiparesis, and altered levels of consciousness. ^{1 , 4 , 5 , 6 , 7} However, because of the central location of these tumors, they are much more likely to cause early dysfunction of the cranial nerves (CNs), hydrocephalus, and cerebrospinal fluid (CSF) seeding. The most common presenting symptom of brainstem tumors is impairment of the CNs, especially of the facial nerve (CN VII). ^{8 , 9} Because tumors can be small at this time, other etiologies (especially demyelinating disease) are often entertained, which may delay diagnosis because of a reluctance to proceed with more invasive confirmatory tests. ¹⁰ Although thalamic tumors typically cause motor or sensory symptoms, 10% of patients can have clinically significant extrapyramidal symptoms (e.g., tremor, dystonia, chorea, ballismus, and myoclonus). ¹¹

The severe impairment caused by CN palsies in a patient with normal cognitive function results in frequent and severe functional disability, often with much greater impairments in quality of life. ¹² Glossopharyngeal nerve (CN IX) and vagus nerve (CN X) involvement produced by tumors located in the lower brainstem can cause airway compromise, dysphagia, coughing, dysphonia, repeated chest infections, and difficulty maintaining basic nutritional needs. ¹³ These symptoms may improve with tumor treatment, but they can progress rapidly to the point that the patient requires mechanical ventilation. ¹⁴ Early insertion of a tracheostomy or a feeding tube can be helpful in select patients, ¹⁴ especially when it is necessary for them to complete treatments. Although patients often fail the weaning process initially, the continued need for a tracheostomy or a feeding tube is uncommon.

Tumors of the thalamus and pineal regions frequently cause early obstructive hydrocephalus via blockage of the proximate cerebral aqueduct and fourth ventricle ^{9 , 15 , 16} ; in contrast, early hydrocephalus is unusual in pontine gliomas. When hydrocephalus occurs early, CSF diversion can result in long-lasting symptom relief and might be the only treatment needed, especially in the case of tectal gliomas. ¹⁷ More typically, however, CSF diversion is only a component of a more comprehensive treatment plan that includes surgical resection or biopsy. ¹⁸ Ventricular shunting is the most commonly used procedure for permanent CSF diversion in patients with brain tumors. The shunt can be of great value for relieving obstructive symptoms, but it carries the theoretical risk of developing peritoneal seeding via the tubing. Although fewer than 30 documented cases of such abdominal involvement have been reported, most have consisted of tumors in the periventricular area, mainly embryonal and germ cell tumors. ^{19 , 20 , 21} Despite its apparent rarity, the development of tumor seeding has clinically significant consequences, which should spur consideration of other strategies for relieving ventricular obstruction. For example, endoscopic third ventriculostomy can be considered an alternative method of treatment, although it has a somewhat lower success rate than ventriculoperitoneal shunting. ^{16 , 17 , 18 , 19 , 20 , 21} Endoscopic third ventriculostomy has the added value of enabling a biopsy to be performed.

Because of the proximity of thalamus and pineal region tumors to the ventricular system, CSF seeding and distant involvement of the spine and supratentorial sites may be present at the time of diagnosis, ^{22 , 23} although distant involvement is rarely the presenting symptom. ²⁴ Importantly, this manifestation is frequently asymptomatic at the time of presentation, raising the issue of whether screening of the spine by imaging and CSF analysis should be a routine part of the diagnostic work-up. ^{22 , 25} It is our practice to perform both spinal imaging and CSF analysis in the routine work-up of patients with these tumors. Neoplastic cells can be documented in the CSF despite normal-appearing spinal imaging. ²⁶ In addition to cytologic evaluation, biochemical testing can help to identify certain types of tumors, especially germ cell neoplasms. ^{27 , 28} Early documentation of spinal and leptomeningeal involvement can therefore play a major role in determining treatment.

Another unique symptom is sleep cycle disturbance associated with pineal body tumors. ^{29 , 30 , 31} Pineal body–related sleep disturbance can be associated with melatonin hypersecretion, reduced secretion, or an abnormal secretion rhythm. ³² An abnormal sleep pattern is commonly associated with reduced melatonin secretion, which is usually documented after tumor treatment. ³⁰ Detailed clinical evaluation of the sleep disturbance and nocturnal plasma melatonin measurements help to determine treatment. Although clear guidelines are not available, several reports suggest marked improvement in sleep when melatonin is administered to patients with documented low melatonin levels. ^{30 , 31 , 32 , 33} We suggest initiating treatment with small doses of short-acting melatonin (5 mg before bedtime), with gradual upward titration to 10 mg. Other traditional insomnia treatments, such as benzodiazepines or selective serotonin reuptake inhibitors, can also be used. ^{34 , 35}

Thalamic Glioma

Gliomas are the most common intrinsic lesions involving the thalamic area. ³⁶ The 2016 classification from the World Health Organization (WHO) separates pilocytic astrocytomas (grade I) from other diffuse gliomas (grades II–IV) ( Table 22.1 ). ³⁷ Additional studies are needed on this new modification, which depends more on biomarkers than on tissue histology for identification of diffuse gliomas, as it has not yet been fully integrated into treatment protocols.

In general, pilocytic astrocytoma should be treated by surgical resection, if possible, as these tumors can be cured when completely resected. ³⁸ However, when these tumors arise in deep anatomical locations, such as the thalamus and brainstem, operative risks are increased to the point that resection is untenable for most patients. ^{36 , 39} Although radiation is often administered to these patients, it has been our practice to avoid its use as long as possible because of the overall long-term survival associated with this histology. Therefore, in cases of progression, we will initiate treatment with chemotherapy, which can be effective for this tumor type.

Diffuse gliomas can be divided into low grade (WHO grade II) and high grade (WHO grades III and IV). It is widely accepted that thalamic diffuse glioma, regardless of grade, is not a surgical disease because of its high rate of morbidity and mortality. ^{7 , 15 , 36} If the radiologic features are suggestive of a low-grade glioma, observation might be considered. However, we recommend surgical biopsy to confirm the diagnosis and molecular testing to guide future treatment. Because resection is not possible, gliomas in this location are irradiated, as they always have a high risk for progression. ⁴⁰ Considering recent data suggesting that chemotherapy improves the outcome for high-risk supratentorial low-grade gliomas, ⁴¹ one can also make a case that chemotherapy should be combined with radiation.

If the radiologic features are consistent with high-grade gliomas (i.e., enhancement on magnetic resonance imaging and clinically significant vasogenic edema), we recommend maximal safe resection. Once the diagnosis of WHO grade IV glioma is made, then the treatment is similar to what is administered to patients with supratentorial glioblastoma ^{42 , 43} ( Fig. 22.1 ).

Central nervous system lymphomas can also arise in the thalamic periventricular areas and should be considered in the differential diagnosis of any enhancing lesion arising in this area. Preliminary diagnosis of a central nervous system lymphoma can be made on clinical and radiologic grounds, although biopsy is required to confirm the diagnosis. ⁴⁴ The approach is the same as when these lesions occur in other locations. ⁴³

Pineal Parenchymal Tumors

A wide variety of primary tumors involving the pineal area can be subdivided according to histology ( Table 22.2 ). Pineal parenchymal tumors can be classified as pineocytoma (WHO grade I), pineal parenchymal tumors with intermediate differentiation (WHO grades II or III), papillary tumor of the pineal region, and pineoblastoma (WHO grade IV).

Pineocytomas are best treated with surgical resection. ⁴⁵ The long-term survival rate among patients with totally resected tumors, with no added adjuvant therapy, is over 90%. Adding adjuvant radiation to subtotally resected tumors may be considered, but little supporting data can be found for this approach in the medical literature. ⁴⁵ Although surgical intervention can result in considerable morbidity, complete resection should be attempted once a diagnosis is made. ⁴⁶ Recently, stereotactic radiosurgery and chemotherapy have been suggested as alternatives to surgical resection ⁴⁷ on the basis of data obtained prior to the current WHO classification. ⁴⁸

No clear consensus on treatment exists for the relatively rare pineal parenchymal tumors with intermediate differentiation ⁴⁹ because, until recently, reports combined tumors with this histology with lower-grade (pineocytoma) and higher-grade (pineoblastoma) tumors. Therefore, one can justify a range of approaches from safe surgical resection followed by focal radiation to surgical resection followed by craniospinal radiation and chemotherapy. ⁴⁹ Cases document long-term survival after surgery and radiation, but they are often associated with high rates of clinically significant permanent neurotoxicity ( Fig. 22.2 ). ⁵⁰ Additional studies are therefore needed to establish the exact benefit from more intense treatment. In general, the degree of surgical resection and distant involvement (i.e., CSF involvement, ependymal seeding, and spinal involvement) should be taken into consideration before making a final treatment decision.

Pineoblastomas are aggressive neoplasms associated with a 5-year survival rate of only 10%. ⁴⁶ Therefore, they justify aggressive treatment similar to that for patients with medulloblastomas. ⁴⁶ We advocate safe surgical resection followed by adjuvant craniospinal radiation and systemic chemotherapy. ⁴⁶ Multiple reports of cohorts suggest a better prognosis in adults older than age 24 years. ⁵¹ The standard radiation dose is 55 Gy to the tumor (2 Gy per fraction), in addition to craniospinal axis irradiation. The reported systemic chemotherapeutic regimens vary, usually including two to three agents, such as vincristine, cisplatin/carboplatin, cyclophosphamide, etoposide, and lomustine. New strategies, including high-dose systemic therapy with autologous stem cell rescue, radiosurgery, and other noncytotoxic drugs, have been reported to yield promising results, ^{46 , 52 , 53} but it has not yet been determined whether outcomes are better with them than with aggressive regimens that are less demanding.